title: Effect of the kinase inhibitor, H-7, on stress, crossbridge phosphorylation, muscle shortening and inositol phosphate production in rabbit arteries.
abstract: Smooth muscle contractile agents cause large increases in crossbridge phosphorylation (Mp) and cycling rates resulting in the rapid development of stress (force/muscle cross-sectional area). Despite temporal declines in Mp and cycling during continued activation, stress is maintained at high levels. This observation led to several different hypotheses describing the regulation of steady-state stress. One proposal is that protein kinase C regulates stress maintenance, whereas another invokes a steady-state dependence on Ca+(+)-calmodulin-dependent myosin light chain kinase. The aim of this study was to investigate the mechanism of stress-maintenance by analyzing the inhibitory efficacy of a protein kinase C inhibitor, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperizine], on steady-state values of stress, Mp and crossbridge cycling in rabbit renal and femoral arteries. H-7 effectively inhibited steady-state stress produced by KCl (IC50 = 3.7-4.4 microM) and phenylephrine (PhE) (IC50 = 10.6-15.2 microM). Likewise, increases in the level of Mp and the rate of crossbridge cycling induced by both KCl and PhE were significantly reduced by 10 microM H-7. H-7 did not reduce inositol phosphate production stimulated by PhE, but did reduce early stress development thought to be mediated by inositol phosphate-induced mobilization of intracellular calcium. Calcium-induced increases in stress and Mp produced in saponin-skinned artery strips were reduced by less than 50% by 320 microM H-7.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Eastern Virginia Medical School, Norfolk.
authors.forename: P H
authors.initials: PH
authors.lastname: Ratz
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction
chemical_list: D007295:Inositol Phosphates; D007546:Isoquinolines; D010879:Piperazines; D010656:Phenylephrine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D011188:Potassium